This is a revised application for Project by Ross. Human immunodeficiency virus (HIV) and methamphetamine (METH) abuse are associated with cerebral injury. Studies utilizing proton magnetic resonance (MR) spectroscopy in abstinent METH users and HIV+ patients have revealed reduced levels of N-acetylaspartate which may be indicative of neuronal injury or death. However, the mechanism of injury is not well understood. Carbon-13 (13C) MR spectroscopy allows for in vivo measurements of important metabolic processes that may reveal the complex mechanisms of damage. To track metabolism, a ISC-labeled substrate is infused and 13C label incorporation into intermediaries provides information on metabolic pathways. One such pathway is the neuronal tricarboxylic acid cycle (VtcaN), which is a measure of energy metabolism. In addition, glutamate-glutamine cycling (Vgln) can be quantified, providing an estimate of the glutamate neurotransmission rate. In this study, 13C MR spectroscopy will be performed during an intravenous infusion of D-glucose-1-13C to study the effects of METH+ and HIV on Vgln and VtcaN. Twenty HIV+/METH+, 20 HIV+/METH-, 20 HIV-/METH+, and 20 HIV-/METH- healthy controls will be enrolled. HIV+/METH- participants are expected to display decreased Vgln and increased VtcaN, which may be indicative of excessive glutamate neurotransmission and increased glutamate synthesis, respectively. HIV- /METH+ will show increased Vgln and decreased VtcaN reflecting a neuroadaptive response to previous heavy METH use. HIV+/METH+ are expected to have similar metabolic rate profiles as HIV+/METH- because the changes related to HIV are predicted to be of greater magnitude than those due to METH. VtcaN and Vgln will be related to measures of neurocognitive and neuromotor function. Additionally, FMRI brain response and cerebrospinal fluid markers of astrocyte and neuron function will be related to 13C spectroscopy metabolic rates.